The subject invention relates to processes for making benzoic acid compounds having certain substituents.
Benzoic acid compounds having certain substituents are useful as intermediates in processes for making other compounds, including antimicrobial quinolone compounds, and the like.
The subject invention involves processes for making 2,4-difluoro-3-Q1-benzoic acid: 
wherein Q1 is derived from an electrophilic reagent, comprising the steps of:
(a) treating 1-bromo-2,4-difluorobenzene: 
xe2x80x83with a strong, non-nucleophilic base; then treating with an electrophilic reagent which provides Q1, or a functional moiety which is then transformed to Q1, producing 1 -bromo-2,4-difluoro-3-Q1 -benzene: 
xe2x80x83(b) treating the 1-bromo-2,4-difluoro-3-Q1-benzene with an alkali or alkaline earth metal or organometallic reagent; then treating with carbon dioxide, or with a formylating agent followed by oxidation, to produce 2,4-difluoro-3-Q1-benzoic acid.
The subject invention also involves optional additional steps to substitute a non-hydrogen moiety for one or both of the hydrogens attached to the phenyl ring of the 2,4-difluoro-3-Q1-benzoic acid, thus producing: 
Glossary of Terms
Unless otherwise specified, the following terms have the indicated meanings when used in this application.
xe2x80x9cAlkanylxe2x80x9d is an unsubstituted or substituted, linear or branched, saturated hydrocarbon chain radical having from 1 to about 8 carbon atoms, preferably from 1 to about 4 carbon atoms. Preferred alkanyl groups include methyl, ethyl, propyl, isopropyl, and butyl.
xe2x80x9cAlkenylxe2x80x9d is an unsubstituted or substituted, linear or branched, hydrocarbon chain radical having from 2 to about 8 carbon atoms, preferably from 2 to about 4 carbon atoms, and having at least one carbon-carbon double bond.
xe2x80x9cAlkynylxe2x80x9d is an unsubstituted or substituted, linear or branched, hydrocarbon chain radical having from 2 to about 8 carbon atoms, preferably from 2 to about 4 carbon atoms, and having at least one carbon-carbon triple bond.
xe2x80x9cAlkylxe2x80x9d includes alkanyl, alkenyl, alkynyl, and cycloalkyl as defined herein, unless specifically or necessarily structurally limited otherwise or by other restrictions. Alkyl retains this meaning when it is used as part of another word; examples are provided below (e.g., alkylene, haloalkyl). In such words, alkyl can be replaced by any of alkanyl, alkenyl, or alkynyl to narrow the meaning of such words accordingly. Also, as referred to herein, a xe2x80x9clowerxe2x80x9d alkyl is a hydrocarbon chain comprised of 1 to about 4, preferably from 1 to about 2, carbon atoms. Preferred alkyl are alkanyl or alkenyl; more preferred is alkanyl.
xe2x80x9cAlkylenexe2x80x9d is a hydrocarbon diradical. Preferred alkylene includes ethylene and methylene.
xe2x80x9cHeteroatomxe2x80x9d is a nitrogen, sulfur or oxygen atom. Groups containing one or more heteroatoms may contain different heteroatoms.
xe2x80x9cHeteroalkylxe2x80x9d is an unsubstituted or substituted chain radical having from 2 to about 8 members comprising carbon atoms and at least one heteroatom.
xe2x80x9cCarbocyclic ringxe2x80x9d is an unsubstituted or substituted, saturated, unsaturated or aromatic, hydrocarbon ring radical. Carbocyclic rings are monocyclic or are fused, bridged or spiro polycyclic ring systems. Monocyclic rings contain from 3 to about 9 carbon atoms, preferably 3 to about 6 carbon atoms. Polycyclic rings contain from 7 to about 17 carbon atoms, preferably from 7 to about 13 carbon atoms.
xe2x80x9cCycloalkylxe2x80x9d is a saturated or unsaturated, but not aromatic, carbocyclic ring radical. Preferred cycloalkyl groups are saturated, and include cyclopropyl, cyclobutyl and cyclopentyl, especially cyclopropyl.
xe2x80x9cHeterocyclic ringxe2x80x9d is an unsubstituted or substituted, saturated, unsaturated or aromatic ring radical comprised of carbon atoms and one or more heteroatoms in the ring. Heterocyclic rings are monocyclic or are fused, bridged or spiro polycyclic ring systems. Monocyclic rings contain from 3 to about 9 carbon and heteroatoms, preferably 3 to about 6 carbon and heteroatoms. Polycyclic rings contain from 7 to about 17 carbon and heteroatoms, preferably from 7 to about 13 carbon and heteroatoms.
xe2x80x9cArylxe2x80x9d is an unsubstituted or substituted aromatic carbocyclic ring radical. Preferred aryl groups include phenyl, 2,4-difluorophenyl, 4-hydroxyphenyl, tolyl, xylyl, cumenyl and naphthyl. Preferred substituents for aryl include fluoro and hydroxy.
xe2x80x9cHeteroarylxe2x80x9d is an unsubstituted or substituted aromatic heterocyclic ring radical. Preferred heteroaryl groups include thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, quinolinyl, pyrimidinyl and tetrazolyl.
xe2x80x9cAlkoxyxe2x80x9d is an oxygen radical having a hydrocarbon chain substituent, where the hydrocarbon chain is an alkyl (i.e., xe2x80x94O-alkyl or xe2x80x94O-alkanyl). Preferred alkoxy groups are saturated, and include methoxy, ethoxy, propoxy and allyloxy.
xe2x80x9cAcylxe2x80x9d is a radical formed by removal of the hydroxy from a carboxylic acid (i.e., R-carbonyl or Rxe2x80x94C(O)xe2x80x94). Preferred acyl groups include, for example, acetyl, formyl, and propionyl.
xe2x80x9cHaloxe2x80x9d, xe2x80x9chalogenxe2x80x9d, or xe2x80x9chalidexe2x80x9d is a chloro, bromo, fluoro or iodo atom radical.
xe2x80x9cOptical isomerxe2x80x9d, xe2x80x9cstereoisomerxe2x80x9d, xe2x80x9cdiastereomerxe2x80x9d as referred to herein have the standard art recognized meanings (Cf., Hawley""s Condensed Chemical Dictionary 11th Ed.).
It is recognized that the skilled artisan in the art of organic chemistry can readily carry out standard manipulations of organic compounds without further direction; that is, it is well within the scope and practice of the skilled artisan to carry out such manipulations. These include, but are not limited to, reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, esterification and saponification and the like. Examples of these manipulations are discussed in standard texts such as March, Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (Vol. 2), Fieser and Fieser, Reagents for Organic Synthesis (16 volumes), L. Paquette, Encyclopedia of Reagents for Organic Synthesis (8 volumes), Frost and Fleming, Comprehensive Organic Synthesis (9 volumes) and the like.
The skilled artisan will readily appreciate that certain reactions are best carried out when other functionality is masked or protected in the molecule, thus avoiding any undesirable side reactions and/or increasing the yield of the reaction. Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many of these manipulations can be found for example in T. Greene, Protecting Groups in Organic Synthesis. Of course, amino acids used as starting materials with reactive side chains are preferably blocked to prevent undesired side reactions.
The starting material for the subject invention processes is 1-bromo-2,4-difluorobenzene: 
A first step of the subject processes is to provide a non-hydrogen moiety (Q1) in the 3-position of the starting material to produce 1-bromo-2,4-difluoro-3-Q1-benzene: 
The 1-bromo-2,4-difluorobenzene is treated with a strong, non-nucleophilic base, typically in an aprotic solvent. This base may be any base useful in permutational hydrogen-metal exchange. Preferred bases include lithium diisopropylamide (LDA), lithium 2,2,6,6-tetramethylpiperidide (LiTMP), lithium bis(trimethylsilyl)amide (LTSA), t-butoxide, or other known bases for this purpose. Suitable bases are known in the literature, and can be found in common reference texts as non-nucleophilic bases. Most preferred is LDA, which produces intermediates that are reasonably stable over a range of times and temperatures. It is preferred that this reaction be carried out at a temperature of above about xe2x88x9280xc2x0 C. and no more than about 40xc2x0 C., more preferably no more than about room temperature, most preferably no more than about xe2x88x9240xc2x0 C. Temperature may vary with the base used; for example, the most preferred reaction temperature is about xe2x88x9265xc2x0 C. with LDA. Reaction times may be up to about 24 hours, more preferably are about 2 hours. Most preferably the process is carried on as soon as it is apparent that the resulting benzene derivative may proceed to the next step in the process. It is also preferred that this reaction take place under an inert atmosphere.
After the base has reacted with the 1-bromo-2,4-fluorobenzene, an electrophilic reagent provides the desired Q1 substituent or a functional moiety which can be transformed into the desired Q1 substituent. Non-limiting examples of electrophilic reagents and the resulting Q1 substituent are shown in the following table:
Typically, the electrophilic reagent is added to the previous reaction mixture while it is still at the temperature indicated above for that reaction. The resulting mixture is allowed to warm under ambient conditions to ambient temperature; this typically takes at least about ten minutes, but no more than about 24 hours, usually no more than about 2 hours. The reaction is complete within that time.
Solvents suitable for these first-step reactions are typically aprotic. Preferably these solvents are compatible with the bases used in the reactions. Preferred solvents include the ethers (e.g., diethylether), glymes, dioxane, and especially tetrahydrofuran (THF). Such solvents are known in the art, and suitable substitutions are made depending on the base, electrophile, and the polarity and solubility characteristics of the reactants and resulting compound.
Other Q1 moieties can be derived from those in the above table by using additional reaction steps well-known to the skilled chemist. Non-limniting examples include alkoxy or acyloxy Q1 moieties derived from the hydroxy; alkenyl, hydroxyalkyl, and aminoalkyl moieties derived from the formyl; and trifluoroalkyl, amide, and imidazoyl moieties derived from the carboxyl.
Preferred Q1 moieties include alkanyl, alkenyl, aryl, halo, hydroxy, alkoxy, acyloxy, alkanylthio, formyl, carboxyl, and carboxylate; more preferred are alkanyl, halo, hydroxy, alkoxy, acyloxy, alkanylthio, fornyl, carboxyl, and carboxylate. Still more preferred Q1 moieties include alkanyl, halo, hydroxy, alkoxy, and alkanylthio. Preferred Q1 alkanyl moieties have from 1 to about 2 carbon atoms; methyl is preferred. Preferred Q1 alkenyl moieties have from 2 to about 4 carbon atoms; ethenyl is preferred. All Q1 alkyl moieties are preferably unsubstituted or substituted with from 1 to about 3 fluoro moieties. More preferred Q1 is selected from fluoro, chloro, methyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, and trifluoromethoxy. Still more preferred Q1 is selected from methyl, methoxy, and chloro; especially either methoxy or chloro.
The 1-bromo-2,4-difluoro-3-Q1-benzene produced in step 1 above is then optionally purified by conventional purification steps, such as distillation, extraction, chromatography, or a combination thereof, or with other known steps. Distillation is a preferred purification step at this stage in the subject processes.
In a second step of the subject invention processes, the 1-bromo-2,4-difluoro-3-Q1-benzene from the above first step is converted to the corresponding benzoic acid, 2,4-difluoro-3-Q1-benzoic acid: 
This benzoic acid is prepared by treating the 1-bromo-2,4-difluoro-3-Q1-benzene compound with an equivalent of an alkali or alkaline earth metal or organometallic reagent useful in permutational halogen-metal exchange, typically in an aprotic solvent (preferably the same solvent as used for the first step). Suitable reagents are known in the literature, and can be found in common reference texts. Preferred strong base reagents include metals such as lithium, sodium, potassium, and magnesium; and lower alkanyl lithiums, such as methyllithium, ethyllithium, and n-butyllithium. The most preferred strong base for this reaction is n-butyllithium, which produces intermediates that are reasonably stable over a range of times and temperatures. It is preferred that the temperature for this reaction be at least about xe2x88x92800xc2x0 C. and no more than about 40xc2x0 C., more preferably no more than about room temperature, most preferably no more than about xe2x88x9240xc2x0 C. Temperature may vary with the base used; for example, the most preferred reaction temperature is about xe2x88x9270xc2x0 C. with n-butyllithium. Reaction times may be up to about 24 hours; more preferably are at least about 10 minutes, and no more than about 30 minutes. Most preferably the process is carried on as soon as it is apparent that the resulting intermediate derivative may proceed to the next step in the process. It is also preferred that this reaction take place in an inert atmosphere.
The resulting reaction mixture is then preferably treated with carbon dioxide to produce the target 2,4-difluoro-3-Q1-benzoic acid compound. Alternatively, the reaction mixture is then treated with a formylating agent, such as a formamide, preferably N,N-dirnethylformamide (DMF). These reactions are usually exothermic and proceed rapidly. To prevent side reactions, it is preferred that the temperature be maintained at those indicated in the previous paragraph by cooling the reaction mixture. The time required for this reaction is limited primarily by the cooling capacity of the equipment and procedures used. The carbon dioxide or DMF must be added slowly enough to insure that the reaction mixture does not overheat. If carbon dioxide is used, the resulting benzoic acid compound is useful without farther purification after a typical work up.
If DMF or a similar formylating compound is used, the resulting benzaldehyde compound is oxidized to the corresponding benzoic acid via oxidation. This can be achieved by exposure of the benzaldehyde compound to air, or by using other known oxidizing reagents, such as chromic acid or potassium permanganate. The oxidation reaction is preferably carried out in a non-ether solvent; preferred solvents include halogenated solvents, such as dichloromethane and chloroform, and aromatic solvents, such as benzene and toluene. The oxidation reaction is preferably carried out at about ambient temperature, but may be carried out at temperatures up to the reflux temperature of the solvent. The same resulting benzoic acid compound is used without further purification after a typical work up.
The subject invention also involves processes for making 2,4-difluoro-3-Q1-5-Q2-6-Q3-benzoic acid: 
wherein either or both Q2 and Q3 are moieties other than hydrogen, from the above 2,4-difluoro-3-Q1-benzoic acid (structure (3)).
Preferred Q2 moieties include hydrogen, iodo, bromo, chloro, hydroxy, alkoxy, nitro, amino, alkyl, cyano and acyl. More preferred Q2 include hydrogen, bromo, chloro, hydroxy, alkoxy, amino, alkanyl, alkenyl, and cyano. Still more preferred Q2 include hydrogen, bromo, hydroxy, alkanoxy, alkanyl, and cyano. Alkanyl, alkenyl, and alkanoxy moieties are preferably unsubsituted or substituted with from 1 to about 3 fluoro, or alkanyl and alkenyl may be substituted with one amino or one hydroxy or lower alkoxy. More preferred still Q2 include hydrogen, hydroxy, bromo, unsubstituted methyl, and methyl substituted with from one to three fluoro.
Preferred Q3 moieties include hydrogen, halo, amino, hydroxy, alkoxy, alkyl, alkanylthio, formyl, carboxyl, carboxylate, and aryl. More preferred Q3 include hydrogen, halo, hydroxy, lower alkanoxy, and lower alkanyl.
For the above Q3 moieties, alkanyl and alkanoxy moieties are preferably unsubsituted or substituted with from 1 to about 3 fluoro, or alkanyl may be substituted with one amino or one hydroxy. Still more preferred Q3 include hydrogen, amino, hydroxy, chloro, unsubstituted methyl, and methyl substituted with from one to three fluoro.
In an optional third step of the subject invention processes, the 2-4-difluoro-3-Q1-benzoic acid compound prepared in the above second step is amenable to derivatization of the 5-position, thus producing 5-Q2-2,4-difluoro-3-Q1-benzoic acid. The 5-position is preferentially derivatized before the 6-position; the amount of reactant is preferably limited so that only the 5-position is derivatized. If the same moiety is desired in both the 5- and 6-positions, excess reactant is used in this optional third step, thus producing 5,6-diQ2-2,4-difluoro-3-Q1-benzoic acid.
If derivatization of the 5-position, or both the 5- and 6-positions, is desired, the reactions chosen depend on the desired functionality, for example: Halo: 
Where Z is a halo, preferably bromo. This reaction occurs under acidic conditions, such as in acetic acid, preferably with a halide activating reagent, such as a silver reagent (e.g., AgNO3). Hydroxy and alkoxy: 
5-Bromo-2-4-difluoro-3-Q1-benzoic acid, made as indicated above, is treated with n-butyllithium, then with lithium t-butyl hydroperoxide to give, after work-up, 5-hydroxy-2-4-difluoro-3-Q1-benzoic acid The corresponding alkoxy compound is readily made by converting the hydroxy moiety to an alkoxy moiety by any known method, e.g. reaction with alkyl iodide or dialkyl sulfate in acetone/water in the presence of base. 
5-Bromo-2,4, difluoro-3-Q1-benzoic acid is treated with n-butyllithium, then with alkanyl (R) iodide to afford 5-alkanyl-2,4-difluoro-3-Q1-benzoic acid. 
Alternatively, 5-bromo-2,4-difluoro-3-Q1-benzoic acid ethyl ester is treated with R-trialkanyltin, where R is alkanyl (preferably the same as for the trialkanyl), alkenyl or aryl, in presence of palladium II or 0 as catalyst in dimethylformamide to afford 5-alkyl-2,4-difluoro-3-Q1-benzoic acid ethyl ester or 5-aryl-2,4-difluoro-3-Q1-benzoic acid ethyl ester. 
Nitration occurs via treatment with activated nitric acid, such as in a mixture of nitric and sulfuiric acids. Reduction of the nitro moiety to an amino moiety may be performed via any appropriate reduction process. Cyano: 
5-Bromo-2,4-difluoro-3-Q1-benzoic acid is treated with copper cyanide in a dipolar aprotic solvent like DMF to afford 5-cyano-2,4-difluoro-3-Q1-benzoic acid. 
Alternatively, 5-amino-2,4-difluoro-3-Q1-benzoic acid is treated with sodium nitrite in a solution of sulfuric acid. The resulting diazoniumn salt is then treated with copper cyanide to afford 5-cyano-2,4-difluoro-3-Q1-benzoic acid. 
Preparation of acyl compounds is accomplished by introducing an acylating reagent, for example Rxe2x80x2COCl (where Rxe2x80x2 is an alkyl or aryl), preferably in the presence of a Lewis acid, for example AlCl3.
Once the 5-position is derivatized with a Q2 other than hydrogen, the 6-position can be derivatized with a Q3 other than hydrogen, if that is desired. Therefore, in an optional fourth step of the subject invention processes, a non-hydrogen Q3 moiety may be incorporated, thus producing a benzoic acid compound of structure: 
This is preferably eved by using reaction conditions similar to the appropriate immediately preceding methods for Q2, thus achieving the Q3 moiety desired: halo, hydroxy, alkoxy, alkanyl, nitro, amino, cyano, or acyl.
If a non-hydrogen Q3 moiety is desired, while retaining Q2 as hydrogen, a different optional third step of the subject invention processes is used to derivatize the 6-position but not the 5-position, thus producing 6-Q3-2,4-difluoro-3-Q1 benzoic acid.
An example of a preferred method for derivatizing the 6-position but not the 5-position is by using the following scheme: 
2-4-Difluoro-3-Q1-benzoic acid is treated with thionyl chloride to afford the corresponding benzoyl chloride, which is then treated with 2-arnino-2-methyl-1-propanol to give the corresponding amide. This amide is then cyclized into a 2-oxazoline using thionyl chloride. The resulting compound is then ortho-lithiated using LDA, and the resulting lithiated compound is treated with the desired electrophile. Finally, the 2-oxazoline is hydrolyzed to regenerate the carboxyl moiety.
Preferred electrophiles usefull in the above scheme are those listed in above Table 1, each of which results in Q3 being the moiety listed as Q1 for such electrophile in the table.